Potassium channels play an important role in the physiological and pharmacological control of cellular membrane potential. Amongst the different types of potassium channels are the ATP-sensitive (K.sub.ATP -) channels which are regulated by changes in the intracellular concentration of adenosine triphosphate. The K.sub.ATP -channels have been found in cells from various tissues such as cardiac cells, pancreatic cells, skeletal muscles, smooth muscles, central neurons and adenohypophysis cells. The channels have been associated with diverse cellular functions for example hormone secretion (insulin from pancreatic beta-cells, growth hormone and prolactin from adenohypophysis cells), vasodilation (in smooth muscle cells), cardiac action potential duration, neurotransmitter release in the central nervous system.
Modulators of the K.sub.ATP -channels have been found to be of importance for the treatment of various diseases. Certain sulphonylureas, which have been used for the treatment of non-insulin-dependent diabetes mellitus act by stimulating insulin release through an inhibition of the K.sub.ATP -channels on pancreatic beta-cells.
The potassium channel openers, which comprise a heterogeneous group of compounds, have been found to be able to relax vascular smooth muscles and have therefore been used for the treatment of hypertension.
In addition, potassium channel openers can be used as bronchodilators in the treatment of asthma and various other diseases.
Furthermore, potassium channel openers have been shown to promote hairgrowth, and have been used for the treatment of baldness.
Potassium channel openers are also able to relax urinary bladder smooth muscle and therefore, can be used for the treatment of urinary incontinence. Potassium channel openers which relax smooth muscle of the uterus can be used for treatment of premature labour.
By acting on potassium channels of the central nervous system these compounds can be used for treatment of various neurological and psychiatric diseases such as Alzheimer, epilepsia and cerebral ischemia.
Further, the compounds are found to be useful in the treatment of benign prostatic hyperplasia, erectile dysfunction and in contraception.
Compounds of the present invention, which inhibit insulin secretion by activating potassium channels of the beta-cell can be used in combination with other compounds which may be used to treat non-insulin dependent diabetes mellitus and insulin dependent diabetes mellitus. mellitus including prevention or slowing of progression of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Examples of such compounds are short and long acting insulins, insulin analogues, insulin sentizers, insulin secretagogues as well as orally active hypoglycaemic agents such as sulphonylureas, e.g. glibenclamide and glipizide; biguanides, e.g. metformin; benzoic acid derivatives, e.g. repaglinide; thiazolidinediones, e.g. troglitazone, rosiglitazone, pioglitazone and ciglitazone; glucagon like peptide 1 (GLP-1), GLP-1 derivatives and GLP-1 analogues; inhibitors of .alpha.-glucosidase, e.g. acarbose and voglibose, inhibitors of hepatic enzymes responsible for the biosynthesis of glucose, e.g. glycogen phosphorylase inhibitors.
Since some K.sub.ATP -openers are able to antagonize vasospasms in basilar or cerebral arteries the compounds of the present invention can be used for the treatment of vasospastic disorders such as subarachnoid haemorrhage and migraine.
Potassium channel openers hyperpolarize neurons and inhibit neurotransmitter release and it is expected that the present compounds can be used for the treatment of various diseases of the central nervous system, e.g. epilepsia, ischemia and neurodegenerative diseases, and for the management of pain.
Recently, it has been shown that diazoxide (7-chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide) and certain 3-(alkylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide derivatives inhibit insulin release by an activation of K.sub.ATP -channels on pancreatic beta-cells (Pirotte B. et al. Biochem. Pharmacol, 47, 1381-1386 (1994); Pirotte B. et al., J. Med. Chem., 36, 3211-3213 (1993); PCT Publication No. WO 97/26265. Diazoxide has furthermore been shown to delay the onset of diabetes in BB-rats ( Vlahos WD et al. Metabolism 40, 39-46 (1991)). In obese zucker rats diazoxide has been shown to decrease insulin secretion and increase insulin receptor binding and consequently improve glucose tolerance and decrease weight gain (Alemzadeh R. et al. Endocrinol. 133, 705-712, 1993). It is expected that compounds which activate K.sub.ATP -channels can be used for treatment of diseases characterised by an overproduction of insulin and for the treatment and prevention of diabetes.
Certain 1,2,4-benzothiadiazine 1,1-dioxides have been proposed to act as potential .alpha.1-adrenoceptor antagonists (Chern, J.-W. et al, J. Med. Chem. (1998), 41, 3128-41).
3-(Alkylamino)-4H-pyrido[4,3-e]-1,2,4-benzothiadiazine 1,1-dioxides have been described recently (Neill, C. G. et al, Tetrahedron (1998), 54, 13645-13654) and Pirotte, B et al, J. Med. Chem. (1998), 41, 2946-2959).
International PCT Publication No. WO 97/26265 discloses a class of fused 1,2,4-thiadiazine and fused 1,4-thiazine derivatives being useful in the treatment of various diseases acting as potassium channel openers.
1,4-Benzothiazin-2-carbonitriles (El-Taweel et al., Arch. Pharmacol. Res., 13, 261-264 (1990), Liso et al., Synthesis, 1983, 755-757, Liso et al., J. Chem. Soc. Perkin I, 1983, 567-572, Liso et al., J. Heterocycl. Chem., 17, 793 (1980), Kano et al., Heterocycles, 12, 681-684 (1979) and Liso et al., J. Heterocycl. Chem., 18, 279 (1981)), furo[3,2-b]-1,4-carbonitrile 1,1-dioxides (Stephens and Sowell, .Heterocycl. Chem. 34, 857-860 (1997)), thieno[3,2-b]-1,4-thiazine 1,1-dioxides (Sthephens and Sowell, J. Heterocycl. Chem. 35, 927-931 (1998)), pyrrolo[3,2-b]-1,4-thiazine 1,1-dioxides (Wang, Bayomi and Sowell, Pakistan J. Sci. Ind. Res. 31, 242-244 (1988)) and 2,3-dihydro-1,4-benzothiazin-2-carbonitrile 1,1-dioxides (V. Baliah and S. Ananthapadmanabhan, Indian J. Chem., 10, 917-918 (1972)) have been described, but not as acting as potassium channel openers.